This application is a 371 of PCT/US96/13210 filed Aug. 12, 1996
The present invention relates to compositions containing quinazolinones. More particularly, the present invention relates to a composition for attenuating vascular endothelial cell proliferation and tube formation and hence angiogenic-associated diseases, as well as for treating human malignancies, i.e., inhibiting primary tumor growth, tumor progression and metastasis, comprising as active ingredient therein a quinazolinone derivative as herein defined.
In U.S. Pat. No. 3,320,124, issued in 1967, there is described and claimed a method for treating coccidiosis with quinazolinone derivatives. Halofuginone, otherwise known as 7-bromo-6-chloro-3-[3-(3-hydroxy-2-piperidinyl)-2-oxopropyl]-4(3H)-quinazo linone, was first described and claimed in said patent by American Cyanamid Company, and was the preferred compound taught by said patent and the one commercialized from among the derivatives described and claimed therein.
Subsequent U.S. Reissue Pat. No. 26,833 and U.S. Pat. Nos. 4,824,847; 4,855,299; 4,861,758 and 5,215,993 all relate to the coccidiocidal properties of halofuginone. U.S. Pat. No. 4,340,596 teaches that halofuginone can also be used for combatting theileriosis.
In 1991, one of the present inventors published an article reporting that reduced collagen synthesis was noted and identified as an important causitive factor in the skin tearing and reduced skin strength of fowl treated with halofuginone, administered in the amounts recommended for use as a coccidiostat. It was also found that, at the cellular level, halofuginone suppressed collagen synthesis by avian skin fibroblasts [I. Granot, et al., Poult. Sci., Vol. 70, pp. 1559-1563 (1991)].
At that time, however, it was neither taught, recognized or suspected that halofuginone or the related quinazolinone derivatives taught in U.S. Pat. No. 3,320,124 could be effectively used for treatment of fibrotic diseases, as well as for treatment of restenosis, glomerulosclerosis, and angiogenesis-dependent diseases.
Clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), pulmonary and hepatic fibrosis and a large variety of autoimrnune disorders, are distinguished by excessive production of connective tissue, which results in the destruction of normal tissue architecture and function. These diseases can best be interpreted in terms of perturbations in cellular functions, a major manifestation of which is excessive collagen deposition.
It is generally recognized that at present, most treatments of fibrotic diseases are ineffective and have little effect upon their inexorable pathological progression. Various attempts have been made in order to reduce collagen deposition in the extracellular space. As is known, progressive fibro-proliferative diseases exhibit excessive production of connective tissues. The crucial role of collagen in fibrosis has prompted attempts to develop drugs that inhibit its accumulation [K. I. Kivirikko, Annals of Medicine, Vol. 25, pp. 113-126 (1993)].
Such drugs can act by modulating the synthesis of the procollagen polypeptide chains, or inhibit some specific post-translational events, which will lead either to reduced formation of extra-cellular collagen fibers or to an accumulation of fibers with altered properties. Only a few inhibitors of collagen synthesis are available, despite the importance of this protein in sustaining tissue integrity and its involvement in various disorders.
Cytotoxic drugs have been used in an attempt to slow collagen-producing fibroblast proliferation [J. A. Casas, et al., Ann. Rhem. Dis., Vol. 46, p. 763 (1987)], among them colchicine, which slows collagen secretion into the extracellular matrix [D. Kershenobich, et al., N. Engl. J. Med., Vol. 318, p. 1709 (1988)] and inhibitors of key collagen metabolism enzymes [K. Karvonen, et al., J. Biol. Chem., Vol. 265, p. 8414 (1990); C. J. Cunliffe, et al., J. Med. Chem., Vol. 35, p. 2652 (1992)].
Unfortunately, none of these inhibitors are collagen-type specific. Also, there are serious concerns about the toxic consequences of interfering with biosynthesis of other vital collagenous molecules, such as Clq in the classical complement pathway, acetylcholine esterase of the neuro-muscular junction endplate, conglutinin and pulmonary surfactant apoprotein.
Other drugs which can inhibit collagen synthesis, such as nifedipine and phenytoin, inhibit synthesis of other proteins as well, thereby non-specifically blocking the collagen biosynthetic pathway [T. Salo, et al., J. Oral Pathol. Med., Vol. 19, p. 404 (1990)].
Collagen cross-linking inhibitors, such as .beta.-amino-propionitrile, are also non-specific , although they can serve as useful antifibrotic agents. Their prolonged use causes lathritic syndrome and interferes with elastogenesis, since elastin, another fibrous connective tissue protein, is also cross-linked. In addition, the collagen cross-linking inhibitory effect is secondary, and collagen overproduction has to precede its degradation by collagenase.
In our U.S. Pat. No. 5,449,678, there is described and claimed a method for the treatment of a human patient suffering from a fibrotic condition, restenosis and glomeruloscierosis, comprising administering to the patient a composition comprising a pharmaceutically effective amount of a pharmaceutically active compound of formula I: ##STR2## wherein: n=1 or 2; R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy;
R.sub.2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and PA2 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl; PA2 R.sub.2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and PA2 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl; PA2 R.sub.2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and PA2 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl; PA2 R.sub.2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and PA2 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl;
effective to inhibit collagen type I synthesis.
After further research and development, it has now been discovered that halofuginone can be used to attenuate neovascularization, as well as for treating human malignancies. It is therefore believed that the other quinazolinone derivatives described and claimed in U.S. Pat. No. 3,320,124, the teachings of which are incorporated herein by reference, have similar properties.